CA2124209A1 - A new preparation with an acrylic-based adhesive copolymeric matrix for the transdermal delivery of estradiol - Google Patents
A new preparation with an acrylic-based adhesive copolymeric matrix for the transdermal delivery of estradiolInfo
- Publication number
- CA2124209A1 CA2124209A1 CA002124209A CA2124209A CA2124209A1 CA 2124209 A1 CA2124209 A1 CA 2124209A1 CA 002124209 A CA002124209 A CA 002124209A CA 2124209 A CA2124209 A CA 2124209A CA 2124209 A1 CA2124209 A1 CA 2124209A1
- Authority
- CA
- Canada
- Prior art keywords
- estradiol
- matrix
- foil
- transdermal
- outer covering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The invention is represented by a transdermal medicated patch for the extended release of 17.beta.-estradiol to the skin. The transdermal patch is formed by an outer covering, a matrix containing from 1 % to 5 % (w/w) 17.beta.-estradiol, and a protective liner which is removed before use. The matrix is formed of pressure sensitive adhesive acrylic copolymers, in which the active ingredient is dissolved or dispersed. The acrylic copolymers are obtained by radical polymerization of 2-ethylhexyl acrylate, methyl acrylate, acrylic acid, vinyl acetate, hydroxyethyl acrylate or a mixture thereof. Optionally quantities of less than 0.5 % (w/w) of other substances may be added.
Description
WO 93/l07, ' pc~lEps2/n27~
r~ O 9 TRANSDERMAL ESTRADIOL DELIYEPcY SYSTEM :~
Introduction .
Ovar~an secretion of 17~-estradiol is lacking in pos~mer~opau&al ;
women. In many women this physiologioal p~henomenon indu.~es progressive hypotrophy of the urogeni~al system as ~ wel l as characteristic vas~motor symptoms, often fol lowed by ::
osteop~rosis affectin~ particularly the v~rtebral ~olumn, These cl imacteric symptoms oan~ be prevented by an exogeno:us estrogen-based hormone replacement ~herapy. ~However~ the :oral administration ~ 1713-estradiol (hereinafter referred ~to a;~ ~ ~
"esPradiol") has problems, since: the hormon~ is~ modi~led in~ the~ -i~testine and in the 1 iver and produces high bl~ood lPvels of ~ltS
me~abolite, such as estradiol sulfa~e, ~ estrone and es~r~ne -sulfate which may accumulate in the~ organism, if ~the;: .~`
adminis~ration is prolonged. One of the undesired ef~ects of the oral administration of estradiol is the increased synthecis by the liver of proteins, inc:luding the substr~te of renin, with a possib~e consequent increase in ar~erial pressure, Th~ oral route can be bypassed by the transdermal adminis~ration of estradiol, which de~i~ers the active ingredient directly into the $ystemic circulation. However, the diffu~ion of estradiol T'~Tl~ SH~E~
WO~3/1077' PCT~EP~2/027l~
¦ 2 ! ¦ ~ sJ 9 through the skin .is difficult. To improve it, a sp~cial transdermal systems must b~ deve~oped that can enhance the absorption of estrad~ol, such as an especially designed, estradiol containing, pressur~- sensitive adhesi Ye patch, i~e. an Estradiol Transdermal Pa~ch (hereinafter referred ~o as "OTP"3.
The OTP represents a considerable therapeutic progress1 over ~h~
conventional oral administration, since it avoids the "~irst pass effect" and delivers estradiol directly into the sy~temic circulation in quanti~ies comparable to those which ar~
physiologically produced by the ovariesO
A widely used OTP is represented by a reservoir in which e's~radiol is dissolved in ethano~ ge~atinised with, for ex~mple, hydroxypropyl cellulose. Th~ reservoir is eon~ained by a membrane, ~hrough which estradiol diffuse~ ~o the skin. In this sys~em the membrane be~omes ~h~ diffusion-rate limi~ing compon~nt of ~he OTP, as it is the c~se of an QTP already on the mark~t.
Various patents have be~n applield for in connection with OTPs provided wi~h diffusion-rate 1 imit7ng rnembranes and the use of solvents such as ethanol, alone or in mix~ure, for dissolvin~3 or dispersing estradiol in the druy r~servoir, and for improving its absorption through the skin. Thus, for example, GB patent 2158 355 deseribes the use of a combination o~ propylene ~lycol and glycerol in variable r~tios; U5 patent 4 658 343 describes th~ use of polye~hyl~ne glycol monolaurate as agent for impr~ving the skin-pene~ration o~ estradiol ( "enhancer" ~, and EP
pa~en~ o ~47 146 describes the use of men~hol for the same purpos~
.
The transdermal systems uased on a diffusion-ra~e limiting membranes involve various problems. For instance any small hole ::
in the membrane causes inevitably ~he breakdown of the whvle tr~nsdermal system.
SUBSTIT~JTE S~ s ~ ~
WO 93/1077' pcr/Epg2/o27~w ~ l h~ 2 3 3 These systems often requi re the use of absorption ~nhancers, which ultima~ely act by disrupting ~he intercel lular connections of the superficial layers of the skin. This effect increases the permeabi 1 ity of the skin to the active ~n~redien~ but often causes skin irritation or sensitisation. The absorption enhancers may als~ be absorbed ~hrou0h ~he skin causing ~nwanted systemic side effec~s~
In ~eneral the systems with diffusion-rate limiting membranes do not allow to achieve constant release ra~es of the activ~
ingredient, which is disadvantageous sin~e usually the therapeu~ic treatments r~quirç that the actiYe ingredient is rel~ased over a prolonged period of time.
..
Another possible structure of transdermal sys~ems is that of the so-cal~ed "monolithic" sys~ems. Tn these systems ~he active ingredient is dissolved or disp~3rsed in a "matrix", which becomes the drug reservoir and con~ains also the pressure sensitive adhesive~ which assure the adhesion of the transdermal system to the ski~. In these systems the release of the active ingredient from the matrix takes pla e by dif~usion9 which is driYen by the chemical potential of the ac~ive ingredient resul~ing from the concentra~ion gradien~ and the thermodynamic properties of the components of th~ matrix.
,'',"
Many pat~nts have recently be~n published on OTP based on matrix -systems.
Thus, for example9 EP pa~ent O 379 ~4~ describes an OTP in whi~h the system contains 2X estradiol dispersed in a matrix cons~itu~ed by an acrylic polymer, an athylene/vinyl acet~te copolymer, gums and adhesives. Lecithin, butylene diglycol and propylene diglycol are used as ab~orption enhanc~rs. .:
EP patent O 371 496 describes an OTP in which estradiot is dispersed in a matrix cvns~ituted by acrylic polym~rs, vinyl acetat~, gums and silicone, containing also various enhancer~
such as ol~ic acid, ethanol and ~lycols.
':
' SUE~S~ITUTE SHEE~T
WO 93/1077' PCl`~EP92/Q27~ ~
JP patent 02 ~96 714 describes khe use of a matrix cQnstituted by a copolymer bas~d on 2-ethylhexyl acrylate and vinyl py r ro 1 i done, and abso rpt i on enhanc~ rs cons i st i ng of 1 act i c es~ers formed by Ct - C 20 alcohols.
EP patent 0 341 202 descri bes l;he use of methyl pyrrol i done and eucal yptol as enhan~ers .
A last example is EP-A-88 394.3, which describes a ~r~nsd~rmal patch containing as enhancers polysorbate 80, polyoxyethy~ene ethe rs and a 1 i phat i c a 1 coho 1 s w i ~h h i gh mo 1 ecu 1 ar we i ~ht .
The use of enh~ncers to improve the absorp~ion of estradiol through the skin is clear ~rom ~he quoted patent literature.
In order to avoid the drawbaclcs connected with ~h~ ~nhancers (skin trri~ation, sys~emic side effects~ ~he absorption of ~h~
ac~ive in~r~3dient c~an be improved by in~;r~as~n~ its thermodynamic activity i~ the matrix, for exampls by increa~ing it~ concentration. This, however, often lead~ to supersa~ura'ced matrices due to the 1 imi~ed solubi 1 ity of the acl;ive .
ingredients~ In order to s~;abi 1 ise the supersaturation, additives must be included in the matrix (cfr. for exampl~, DE~
C-3 933 46û). Nevertheless the sys~ems remain in metastable conditions and ~he incorporated active ingredients may crystallis~ during ~ime7 decreasing their thermodynamic activity, whic:h is the driving force ~or diffusion through ~he skin. The physical s~ability of these systems is therefore not predictabla. The crystal1isation of the actiYe ingredien~s may also chan~e the adhesive proper~ies of ~h~ transdermal patch, ~:~
eoP~rdising th~ adhesion of the ma~rix ~o the skin and the relia~le drug absorption. `~
The matrix of "monoli~hic" transdermal patches must ~herefore comply with severa~ prere~uisites. In f~ct the active ingredien~
must be provided by a notable thermodynamic poten~ial and nevertheless it must be stable in tim~. Sinc~ the matrix contains also the pressure sensitive adhesives which stick the patch ~o the skin, it mus~ have good "tack" pr~per~i~s..
SUBSTITUT~ Slt~ IET
WO93/1077~' 212 ~ ~ O PCT~EP92/0271~-1 Neverthaless the patch mu~t be easi ly removabl~ from the skin after use, and during this procedure ~he matrix must remain attached to the ou~er coveri ng and not to ~he ski n . The adhe~ives must not "creep", because in ~his c~se the patch would s~;ick to ~he container. As al ready pointed out, the matrix should nc~ con~ain ab~orption enhanç~rs, in or~er ~o prevent ~kin irrita~ion or sensi~isation. In addition, obviously, all the componenks of the ma~rix must b~3 wel 1 tolerated by the skin, even after repeated and prol onged appl i cati ons of th~ patches .
De~crlptis:~n of ~he pr~sent invention S~veral formulations were inves~igat~d in ord~r to optimize the matrix of the QTP described in this invention. Mos~ formulations were bas~d on acryl ic opolymers, to which differ~nt subs~ances were add~d in order ~o improv~ the adhesive qual ity of ~he matrix, for exarnple hydroabiethylalcohc)l, glycerylester of hydrat d col lophonium, pen~aester of hydrated col lc>phonium, methylester of partial~y hydrated collophonium, or ~-methylstyrol/s~yrol copolyrners. Al l these formul~tions had to be discarded because of crystallisation of ~he a ~ive ingredi~nt or impai rment of i~s release rate ~ -~ ~.Bas~d on this experience a monol ithic ma~rix was developed which represen~s a de~inite improvement over ~he present state of art, since it el iminates or reduces to a minimum ~h~ main di sadvantage~3 of the transdermal patches known up to now and . ., previously described. In ~act ~he nèw invention provides a system f~r the ~ransdermal administra~ion of estradiol which is well tolera~ed, is st ble, is effeçtiv~9 preven~s the crystallisation of the active ~ngredient ln the matrix, ensures adequate and extended levels of the active in~redien~ in blood, and has very good tack and adhesiYe properties.
SI~STITIJTE SH~T
WO~3/1077' ~ PCr/EP9~/02 A~cording to the invention the above mentioned features were provided by a transdermal patch for the ex~en~ed release of 17~-estradiol onto the ~;kin consisting of:
a) an outer covering (backing foil );
b) pressure-sensitive adh~sive copoiymers c~ns~it-ting ~he ma~rix in which the active ingredient is dissolved or dispersed ( drug reservoi r );
c) a protective liner which is removed at the time of use;
The i nven~i on descri bes a new transdermal patch for ~;he extended re~ase of es~radiol to the ~kin, in wt-ich the active ingredien~
s dissolved or dispers~d in a 5u-~able pressure-sensitiv~
adhesive copolymeric ma~rix, and which surpri~in~ly avoids the need of substances to improve the absorption of ~h~ drug through the skin (enhancers), or of supersaturated solutions o~ the active ingredient, thus preventing problems of skin comp~ti bi l i ty and of stabi l i ty of ~he who~ e sys~em.
A specific embodim~nt concerns a ~ransderrnal rnedic~t~d patch which is charact2rised in that the components of ~he adhesive copolymers are obtained by radical po~ymeri~ation of 2-ethylhexyl acrYlate, methyl acrylate, ac:rylic acid, vinyl acetatet hydro>~ethyl acrylate or mixture thereof, possibly with ~uantities o~ less than 0.5% (w/w) of other ad~itives in the adh~sive copolymers.
A specific embodiment of the invention conc~rns a transdermal medica~ed pa~ch in which the adhesive copolymers o~ ~he matrix ar~ obtained by radical polymerization of (w/w of the matrix) about 50% to 70% ~preferably 55% to 65% and especially 61g6 to 64%) 2-ethylhexyl acrylate, about 2096 to 40% (preferably 24% to 32% and ~special ly 25% t~ 28%) methyl acryla~e, about 2% ~o 8%
(preferab~y 3% to 5% a- especially 4% to ~g6) acrylic acid, abou~ 2% to ~ 0% ( preferabl y 3% tc> 796 and especi al 1 y 4X ~o 5% ) ~Jinyl acetate, and a~o~t 0.~% to 3% (preferably 0.7% to t~5% and especially abol-t 1%) hydroxyethyl acrylate.
SU~TlTlJT~ S~ T
WO 93/1077~ PCI /EP92/027~
?12'120~
Smal 1 quanti ti es of 1 ess than O . 5% of o~her subs~ances may al sc:
be uS~d to i mprove ~h adhesi ve prvperti es and the strength of the mat r i x .
~, According to the invent~on no cross-l inker is used in the adhesive copolyrrer9 such as titanium ac~3ty~as::etonate, as it is slJggested by the prior art3 in order to avoid creeping of khe adhesives onto the removable protective l iner and therefvre stic:king of the patch to its container. The pr~blem of creeping i s surpri si ngl y avoi ded i n the i nventi on by usi ng the desori bed copolymers obtained by radical polymerization.
The OTP according to the invention is characterized by a content.
o~ 17~-estradiol from lX to ~%, pref~rably 2.0% to 2.5%, (wJw3 o~ the weight o~ the adhesive copolymers.
., .
A speci~ic embodiment of the inventiQn concerns a transdermal patch which contains about 4 rmg 17i3-estradiol per 18 to 2Q cm2 of patch area.
A sp~cific embodi-ment of th~ invention of the trancdermal patch comprises an outer covering of suita~le proteetive mat rials, which forms the ext~rnal backing foi l o~ th~ patch and i~
constituted by a foi l of thin, ~lexible and water-impermeable material, preferably selected ~rom th group of polyest r~
polyure~hane, polyethylene andJor polyvinyl chloride.
Final ly, the transdermal pa~ch according to the inventien comprises a removable protec~ive liner, preferably consti~uted by a foil of paper or polyester which is preferably silicon~-coated on one or both sijdes and that is easily removed a~ the time of use without lmp~iring the ~ransdermal patch.
Accvrdiny to the additional emb~diment of the invention, a process is described for the production of a transdermal patch for the extended release of 17~ estradiol to the skin, which is characterized in that pressure-sensitive adhesive copolymers con~aining 1713-estradiot as active ingredient are spread on~Q a SUB~ 5T~
WO ~3/107, ' P(~/EP92/0271~
~12~U9 - 8-removable protective liner and then covt~red by ans:th~r . l.~ner which becomes the outer covering.
A~ternatively the pressure-sensitive adhesive sopolymers containin~ 17~-~s~radiol are spread on a water-impermeable ft~i l which be~om~s ..he outer covering7 and are then cover~d by the protec~ive l iner.
Sti l l alternativ~ly the pr~ssure sensitive adhesive copolymers containin~ t713-~stradiol are spread ~n an in~ermediate liner ~ usual l y a si 1 i coni zed paper sheet ) and ~hen covere~ by the foi l of the outer covering ~o which the copolymers adhere firmly. In the final manufa~turing process the intermediate liner is removed and subs~i~uted by ~he protective liner.
A~cording to a pref~rred embodimen~ of the claimed proces~ the ~ransdermal patch can be produced as fol7~ws: ;
- the pressure-sensitive adhesiYe copolymers ar~ dissolved in an :~
or~nic solvent ~adh~sive mixkure~
17~-estradiol 9 dissolv~d or dispersed in an organic sol~ent or in a mixture of solvents, is dissolved or dispersed in the adhesive mixture by stirring, at a concentration ~rom lX to ~%
(w/w) of ~he dry weight of the pressure-sensitiv~ adhesive copolymers;
- the ob~ained mixture is concen~rated by ~vaporation of some of the s~vents and then spread onto ~he removable pro~ective liner, preferably constituted by a foil of p~per or polyester which isi silicone-coa~id on ~ne or on both sides;
alternatively the mixture is spread on~o the foil of th~ outer covering, constituted by water-im~ermeable materials preferably selected from thei group of po ester, polyurethane7 polyethylene and/or polyvinyl chloride; still al~ernative~y the mixture is spread on an intermediate liner, preferably constitu~ed by a sheet of paper, prefeirably siliconized on one or on both sides;
~r~ 3~
WO93/1077' 21 2 ~1~; 9 PCT/EP92/027~
_ 9 _ - ~he solven~ is evaporated a~ a-~emperature frvm 30' ~o ~O'C
with or without applying a vacuum;
- a ~o11 o~ thin, flexible and wa~er-impermeable material constituting the outer covering is applied, or, alternatively the final proteetive lin~r is appii~d or alternatively the intermediate liner is removed and replaced by the final protectiv~ liner, according one of the three procedures outlined above as examples, - the produced composite medica~ed foi 1 is cu~ into portions of appropriate shape and surface, such ~hat they contain the requirsd ~uantity of the active ingredient suitable for the therapeutic use, and in ~his way th~ final transdermal pa~ch~s are obtai ned .
The appropriate qual i~ative-qua7~itatiYe selection of th~
acryl ic component of the ~inal c opolymer sbtained by radical polym~rization, i.e. 2-e~;hylhexyl acrylate, acrylic acid and hydroxyethyl acrylate, and of vinyl acetate whiGh acts as solvent ~or the active ingredien~, is suitable for a transderm~
system for the extended release of es~radiol which is s~cable in tirne and eloes not give rise to crystal 1 isation of the active i ng red i ent i n the mat r i x .
Moreover, as will be described below, the serum levels of estradi~l in menopausal pa~ients obtained after having applied ~he ~ransdermal patch to their skin7 are more constan~ during ~he application time than during the applicatt~n of a patch proYided wi~h a diffusion-rate limiting membrane and ethanol as enhancer. Surprisin~ly the extent of absorption ~fter the applicatlon of the invented OTP was similar to that of the enhanced system.
Sl~.~BSTlT~JTE~ SHEET
WO93/1077' PCT/EP92~027fl~
~ t~i 9 -- ~o Example 1 (Production of a ~ransd~rmal pa~ch con~aining ~ ~9 of estradi~
The production process of the transdermal patch according to the present invention, con~aining 4 mg o~ 17~e ~radiol a~ the active tngredient per t8 cm2 of pa~ch area (hereinafter referr~d to as "DERMESTRIL"), is illustrated further by the ~ollowing9 non-limiting example.
An adhesive mixture was prepared diss~lvtng in 3 ~itres of ethylacetate a mixture of copolymers obt~ined by radical polymeri~ation of 1038 9 2-ethylhexyl acrylate, ~20 9 methyl acrylate, 6~ 9 acrylic acid, 87 9 vinyl ac~ta~, and 17 9 hydroxyethyl acrylate.
A quantity of 40 9 of 17~ estradiol was dissolved or finely suspended in a mix~ure of solven~s cons~i~uted by 1 litr~ of propan-2-ol and 1.5 litr~s of ethyl a~etate~ This solution was added~ under stirring, to ~he mix~ure of copolymers, prepared as described above.
The mixture was sti rred until a homogeneous mass was obtained and this was euaporated to produce a mixture with a conslst~ncy appropriate for spreading on the appropriate liners. Th~n the adhesive mixture cont~ining the active ingredien~ was spread onto a foil of silicone-coa~ed paper or polyester and dried at a temperature b@kween 30 and 80'C ~o produce a fi~m of matrix wei ghing about 98 g/m2 ~ 5X) as the dry weight, corresp~nding to about 2.2 g of 17~-es~radiol p~r m2 of the dry matrix.
Finally, a polyester foil, about 15 ~m thick, was stuck on the matrix to form the outer covering of the patch.
Individual circular patches having areas of ~8 cm2, each c~n~ining about 4 mg of ~he ac~ive ingredient were cut from the comp~site mediçated foil to form ~he final transdermal patch.
Sl)BSTITlJTE SHEET
WO 93/1077' PCT~EP92/0~7l~
? ~ 2 ~ ~
In ~ummary, the step~ for preparing the estradiol transdermal patch (OTP) as~cording ~o ~he present invention consist substanti al i y of ~
- adding a solution or a fine susp~nsion of estradiol to a suitable mixture o~ copolyrn~3rs of acrylates and vinyl acetate;
- spreading a thin layer of the mixture formed by the dispersion of the active ingredient in the acrylic copolymers on a protec~ive 1iner of silicone-cc~ated paper or polyester to be removed at the ti me of use;
- drying the liquid adhesive film formed by the acrylic copolymers and containin~ estradiol, at a temperature between 3{~ and 80'C in order to ~vapora~e thf~ solvent~ wi~h or without applying vacuum;
- applying a foil of thin, flexible, water imperme~ble material which constitutes the outer coverins of the pa~ch;
- cutting the composite m~dicated foi 1 prod~ced as above described into portions having ~he desired shape and surface, tor .oxample 18 cm2 for patchesl containin~ 4 mg est;radiol;
- alternativ~ procedures are also possible, such ~s spreading the adh~siYe mtx~ure onto the ou~r covering or onto an intermediate liner. The ~ollowing manufaeturing steps are ~hen made in order to produce the appropriate final composite med i cated f o i 1 .
Release of es~radiol in vitrc .
The release of estr~diol from the OTP produced according to the invention ( "DEP~MESTRIL" ) was tested in vitro wi~h the fol lowin~
p rocedu re .
SUB~ UT~ SHE~
, . .. .. .... ,, .. .. , ... . " , , WO 93/11~77' PCT~EP92/0271~
4~
Discs cut from l)ERMESTR~L OTP, with surfaçe ar~as of 6 cm2 and containing about 1.33 mg of estradiol, were applied to a support deposited on the base of the dissolu~lon test apparatus according to USP XXII, consisting of a 1 litre g1ass vessel and ~-;
a rotati ng bl ade .
The di stance between the supps: r~ and ~he bl ade, whi ch rotated at a speed of 50 revol Utl ons per mi nute ~ was 2 . 5 cm and the dissolution l iquid was constituted by ~00 ml of water at 32C.
Portions of 1 ml of the solution were withdrawn at ~!7 4, 6, 8, 12, 24 and 36 ho~rs after the start of the ~xperiment, and the estradiol cc:ntent was determined by HPLC. The test was r~3peated ~;
6 times. `
The quantities of released estradiol, expressed as mi l l i~rams ::
and as percent of the nominal ~ontent of estradiol in DERMESTRIL
at the various times, are given in tabl~
Tabl e Mi l l igrams and percen~ v~ es~radiol released in the in vitro test :
T i me ( h ) mg X of nomi na 7 2 0.6~ 16.5 4 o.95 ~3.
6 1.25 31.2 12 1.70 42.5 . ;~
~4 ~ . 48 6~ . 9 36 3.20 80.
Table 1 ~hows thak frs:)m 6 to 36 hours, the release kinetics is l i near and can be expressed by the equati on R = O . 8966 + O . 0646 x h -~
where ~ _ mg of estradiol released and h - ttme in hours.
SL~ r,~ Z " ~
W093/1077' PCT/EP92/027W
- 13 ~ ~ 2 ~ ~ ~ 9 Table 1 shows also tha~ abowt 30x of the estradiol contained in ~-.
the patch had been released after 6 hours, abou~ 60% aft~r 24 :-hours and about 80% after 36 hours.
Bioavailability of estradiol from DERMESTRIL
The bioavailability s~udy was carried out in postmen~pausal women. DERMESTR~L was compared with an OTP commercially available and characterized by a diffusion rate limi~ing membranP and containing e~hanol as solvent and absorption enhancer (hereinafter called "Reference OTP"). ~-~
., .~ ., Two DERMES~RIL patches prep~red according to the invention, and containing each 4 mg of estradiol per 18 ~-m2 or tWQ Ref~rence OTPs, also containing 4 m~ of estradi~l, were applied on ~h~ :
skin of the s~bject for a ingle application of 96 hours. i:
Studied were 20 subjects and ~he patches were applied according ::
to a cross over design, with a suitable wash-ou~ period be~ween the two treatments.
Estradi~l in blood serum was de~ermined~by a RIA method. The estradiol serum levels ~xpressed in pg/ml are given in figure l and in table 2. Tabl~ 2 gives ~lso the avera~es of the maxtmum . ~
: concentrations found ~C~.x), of the times to ~he pe~k (~x) and ~.
of the area under the c~ncentration/~ime curve: (AUC) in the period 0-96 hours after administra~ion.
":
Sl~E3S~lTUTE SHIEET
WO 93/1077' PCr/EP92/027~ t 3~ - 14 - ~ ~
Tabl e 2 :~
Estradiol levels in serum at various times ~fter the ap~lication of 2 OTPs a~cording to the invention (DFRMESTRIL) or of 2 commercial OTPs (R ference OTP~, Both, D~RMESTRIL and khe :
Reference OTP contain each 4 m~ estradiol. Avera~es and SD of 20 subjects, Estradi ol pp/ml + S~
Hours DERMESTRIL Re~erenGe OTP
O t.96 + 3.94 2.06 ~ 3.81 2 5.34 + 7.B7 31.13 ~ 29.45 ~:
2~.27 + 34.~4 67.65 ~ 4~.~7 8 42.46 ~ 31.~2 6~.91 ~ 2~.86 12 ~5.07 + 46.51 61.35 + 21.26 24 ~1.8~ + 28.63 5~.35 ~ 16.76 36 56.28 ~ 32.87 61.37 + 23.31 48 44.43 ~ 24.13 49.34 + 1~.37 47.74 ~ 39.17 42.78 + 21.19 72 41.02 ~ 22.29 30.48 ~ 15.34 84 4Q.03 + 19.87 22.33 ~ 12.87 :~
96 3~.18 + 19.73 19.85 ~ 9.16 ~`
~08 8.80 ~ 6.51 7.49 + ~.39 120 7.01 ~ 5.91 5.76 + 4.89 ~:
C~x 66.1B + 4~.0 87.35 + 29.87 t~x 35.00 + 19.8 1~.80 + 18.99 ~
AUC ~O-g6 h) 4286 ~ 2409 4268 + 1226 ~-From the results given in table 2 it can be ~.~ncluded that th~
areas under the concentration/time curves (AUC) do not differ significantly aft~r the two ~reatmen~s. In fact the A~C10-96 after DERM~STRIL was 4286 ' ~409 (SD;, and after the Reference OTP was 4268 ~ 1226 (SD).
.~II~ ~TI~II~ ~ ~T `:
WO 93/l077~ PCI /EP92/02711 1 5 - ~ " 3 This ~emonstrates that th~ bioavai labi l ity of estr~diol ~rom ::
DERME~TRXL is the same as that ~rom Reference OTP, and this is a surprisin~ result because DERMESTRIL does not contain absorption enhancers . : ~
Tolerabi l ity by the skin ~-:
The skin tolerability to th~3 C)TP prepared according to the inven~ion was evalua~ed on 10 ~emale guinea pigs weighing between 300 and 400 9. ~-~
The patches were applied to the previously shaved l@f~ scapular region of the animals. An area of patch o~ 2 x 2 cm cut from DERMESTRIL and ~hus containing about 0.~9 mg ~stradiol, was --~
stuck on the shaved skin and l~fl; there fGr about 6 hours. The :
tolera~ility o~ the patch was eva~ua~ed by the appearance of erythema or oedsma after 24 hours of appl ica~ion, according to the fol lowing s~ore~.
Score ERYTHEMA OEDEMA
0 No ef f ect NQ ef f ect Sl i 9ht Sl i ght oedema ~- .
Moderate Modera~e o~dema ~;
3 Intense Severe oedema The test was repea~ed usi ng the same ~;cores after 7 days, i n -~
order ~o re~:ord a possible sensitization induced by the pat~h" ~
-'-"~, The overal 1 swm o~ the scores relating to erythema for the 10 animals was 1 o~ 30, because only 1 animal out of 10 showed a sl ight erythema (30 is the maximum score obtainable) .
No ~nimal presented oedema. ~;
. . .':
SUB~;TITIJTF SH~-~T ~
WO 93~'1077' PCI /EP92~0271i~1 ., In the sensi~isa~ion challenge carried out a~ter 7 days, no an1mal had eryth~ma or oedf~ma, demonstra~in~3 ~hat the patches were wel 1 tolerated and did not induc~ sensi~i~ation under the ex pe r i me nta l cQnd i t i ons .
,.
Examples 2 t~ 4 and Comparative Examples 1 to 7 Table 3 summarizes th~ composi~ion of the matrix of Exa~mples 1 ~o 4 and o~ the C:omparative Examples 1 to 7. The correspondin~
formulations of the matrix containing the cop:>lymers obtained by radical p~lym~rization of the acryl ic compounds are :
quantitatively listed in table 3. Th@ resull;ing OTP~ were tested ;~
for stabi 1 ity and also~ in six human subjects, for adh~sion and -:
skin compatibil~y. The resul~s obtatned with ~he ~leven formulations 3re also reported in ta~le 3.
The resullts clearly show that ~ ormulations No~ 1 ~o 4 and ~:
partiGularly No. 1 exhibit the propert1es require~ for the ~-matrix o~ a "monol ithic" ~ransdermal patch. Conv~rsely oth~r formulations, wh:ich are here l is~ed as Comparative Examples 1 ~o 7, had disadvantage~, for instance discolouration (fort...Jlations No. 6 ~o ~0), unacceptahls skin compatibility (formulation No. ;:
5), ~r una~ceptable tack properties tformulations No. 6, 7, 9 ~-~
and 11 ).
S~ T~3TE ~
W0~3/1077 PCT/EP92/0271~
. ' ` ' ;.;.~. ~J ' - 1 7 ~
Table 3 -~.~
Percentage of monomers in~t~ acrylic copolymers and other substanc~s in differen~ f~rmulations. Properties of the matrix obtained wi~h these copolymers.
Examples Comparative Examples 1 2 3 4 ~ 2 3 4 5 6 7 F~rmulation N~. 1 2 3 4 5 6 7 R 9 10 1 Substances 2-EHA 62.6 6~.5 63.4 57.6 66.9 62.2 63.1 64.0 59.2 56.6 64.2 MA 26.4 33.0 ~05 19.5 0.0 26.4 21.5 16.5 25.1 24.0 16.5 VA 5.6 0.0 9.~ 8.9 28.0 5.6 9.8 1~.0 5.3 5.1 14.0 :~
AA 4.4 5.~ 3.6 3.3 0.0 4.3 3.~ 2.7 4.1 3.9 2.8 ~-GMA 0.0 0.0 0.1 0~1 0.2 0.1 0.1 0.1 0.~ 0.0 0.1 HEA 1.0 0.0 1.8 1.6 5.0 1.0 l.B 2.5 1.0 0.9 2.5 -~
TA 0.0 0.0 - 0-0 0.4 0-3 0.3 0.4 0-4 HR 0.0 0.0 0.0 9.1 0.0 O.o 0.0 0.0 4.8 9.1 0.0 ;;
Fea~ures Estrad. solub. ~ G G G G G G ~ G G G
Discolora~ion ~ + ~ + +
Tack on skin G G M G G B B G B G
Ski n ~ompat . G M M M B G G M G M G .-Legenda: B = Bad; M = Medium; ~ = Good; S = Too strong;
= Presen~; - = Absen~ -Su~stances~
2-E~A = 2-Ethylhexylacrylate MA = Methylacrylate YA - Vi~yl acetate AA = Acrylic acid ~ .
GMA = Glycidylmethacryla~e :
HEA = Hydroxye~hylacry la~e TA = T i tan i um acety 1 acetonate :~
HR = Hydrocarbon resin ,.
.. , . :~.
. ., SL113STITUTE S~IEET -
r~ O 9 TRANSDERMAL ESTRADIOL DELIYEPcY SYSTEM :~
Introduction .
Ovar~an secretion of 17~-estradiol is lacking in pos~mer~opau&al ;
women. In many women this physiologioal p~henomenon indu.~es progressive hypotrophy of the urogeni~al system as ~ wel l as characteristic vas~motor symptoms, often fol lowed by ::
osteop~rosis affectin~ particularly the v~rtebral ~olumn, These cl imacteric symptoms oan~ be prevented by an exogeno:us estrogen-based hormone replacement ~herapy. ~However~ the :oral administration ~ 1713-estradiol (hereinafter referred ~to a;~ ~ ~
"esPradiol") has problems, since: the hormon~ is~ modi~led in~ the~ -i~testine and in the 1 iver and produces high bl~ood lPvels of ~ltS
me~abolite, such as estradiol sulfa~e, ~ estrone and es~r~ne -sulfate which may accumulate in the~ organism, if ~the;: .~`
adminis~ration is prolonged. One of the undesired ef~ects of the oral administration of estradiol is the increased synthecis by the liver of proteins, inc:luding the substr~te of renin, with a possib~e consequent increase in ar~erial pressure, Th~ oral route can be bypassed by the transdermal adminis~ration of estradiol, which de~i~ers the active ingredient directly into the $ystemic circulation. However, the diffu~ion of estradiol T'~Tl~ SH~E~
WO~3/1077' PCT~EP~2/027l~
¦ 2 ! ¦ ~ sJ 9 through the skin .is difficult. To improve it, a sp~cial transdermal systems must b~ deve~oped that can enhance the absorption of estrad~ol, such as an especially designed, estradiol containing, pressur~- sensitive adhesi Ye patch, i~e. an Estradiol Transdermal Pa~ch (hereinafter referred ~o as "OTP"3.
The OTP represents a considerable therapeutic progress1 over ~h~
conventional oral administration, since it avoids the "~irst pass effect" and delivers estradiol directly into the sy~temic circulation in quanti~ies comparable to those which ar~
physiologically produced by the ovariesO
A widely used OTP is represented by a reservoir in which e's~radiol is dissolved in ethano~ ge~atinised with, for ex~mple, hydroxypropyl cellulose. Th~ reservoir is eon~ained by a membrane, ~hrough which estradiol diffuse~ ~o the skin. In this sys~em the membrane be~omes ~h~ diffusion-rate limi~ing compon~nt of ~he OTP, as it is the c~se of an QTP already on the mark~t.
Various patents have be~n applield for in connection with OTPs provided wi~h diffusion-rate 1 imit7ng rnembranes and the use of solvents such as ethanol, alone or in mix~ure, for dissolvin~3 or dispersing estradiol in the druy r~servoir, and for improving its absorption through the skin. Thus, for example, GB patent 2158 355 deseribes the use of a combination o~ propylene ~lycol and glycerol in variable r~tios; U5 patent 4 658 343 describes th~ use of polye~hyl~ne glycol monolaurate as agent for impr~ving the skin-pene~ration o~ estradiol ( "enhancer" ~, and EP
pa~en~ o ~47 146 describes the use of men~hol for the same purpos~
.
The transdermal systems uased on a diffusion-ra~e limiting membranes involve various problems. For instance any small hole ::
in the membrane causes inevitably ~he breakdown of the whvle tr~nsdermal system.
SUBSTIT~JTE S~ s ~ ~
WO 93/1077' pcr/Epg2/o27~w ~ l h~ 2 3 3 These systems often requi re the use of absorption ~nhancers, which ultima~ely act by disrupting ~he intercel lular connections of the superficial layers of the skin. This effect increases the permeabi 1 ity of the skin to the active ~n~redien~ but often causes skin irritation or sensitisation. The absorption enhancers may als~ be absorbed ~hrou0h ~he skin causing ~nwanted systemic side effec~s~
In ~eneral the systems with diffusion-rate limiting membranes do not allow to achieve constant release ra~es of the activ~
ingredient, which is disadvantageous sin~e usually the therapeu~ic treatments r~quirç that the actiYe ingredient is rel~ased over a prolonged period of time.
..
Another possible structure of transdermal sys~ems is that of the so-cal~ed "monolithic" sys~ems. Tn these systems ~he active ingredient is dissolved or disp~3rsed in a "matrix", which becomes the drug reservoir and con~ains also the pressure sensitive adhesive~ which assure the adhesion of the transdermal system to the ski~. In these systems the release of the active ingredient from the matrix takes pla e by dif~usion9 which is driYen by the chemical potential of the ac~ive ingredient resul~ing from the concentra~ion gradien~ and the thermodynamic properties of the components of th~ matrix.
,'',"
Many pat~nts have recently be~n published on OTP based on matrix -systems.
Thus, for example9 EP pa~ent O 379 ~4~ describes an OTP in whi~h the system contains 2X estradiol dispersed in a matrix cons~itu~ed by an acrylic polymer, an athylene/vinyl acet~te copolymer, gums and adhesives. Lecithin, butylene diglycol and propylene diglycol are used as ab~orption enhanc~rs. .:
EP patent O 371 496 describes an OTP in which estradiot is dispersed in a matrix cvns~ituted by acrylic polym~rs, vinyl acetat~, gums and silicone, containing also various enhancer~
such as ol~ic acid, ethanol and ~lycols.
':
' SUE~S~ITUTE SHEE~T
WO 93/1077' PCl`~EP92/Q27~ ~
JP patent 02 ~96 714 describes khe use of a matrix cQnstituted by a copolymer bas~d on 2-ethylhexyl acrylate and vinyl py r ro 1 i done, and abso rpt i on enhanc~ rs cons i st i ng of 1 act i c es~ers formed by Ct - C 20 alcohols.
EP patent 0 341 202 descri bes l;he use of methyl pyrrol i done and eucal yptol as enhan~ers .
A last example is EP-A-88 394.3, which describes a ~r~nsd~rmal patch containing as enhancers polysorbate 80, polyoxyethy~ene ethe rs and a 1 i phat i c a 1 coho 1 s w i ~h h i gh mo 1 ecu 1 ar we i ~ht .
The use of enh~ncers to improve the absorp~ion of estradiol through the skin is clear ~rom ~he quoted patent literature.
In order to avoid the drawbaclcs connected with ~h~ ~nhancers (skin trri~ation, sys~emic side effects~ ~he absorption of ~h~
ac~ive in~r~3dient c~an be improved by in~;r~as~n~ its thermodynamic activity i~ the matrix, for exampls by increa~ing it~ concentration. This, however, often lead~ to supersa~ura'ced matrices due to the 1 imi~ed solubi 1 ity of the acl;ive .
ingredients~ In order to s~;abi 1 ise the supersaturation, additives must be included in the matrix (cfr. for exampl~, DE~
C-3 933 46û). Nevertheless the sys~ems remain in metastable conditions and ~he incorporated active ingredients may crystallis~ during ~ime7 decreasing their thermodynamic activity, whic:h is the driving force ~or diffusion through ~he skin. The physical s~ability of these systems is therefore not predictabla. The crystal1isation of the actiYe ingredien~s may also chan~e the adhesive proper~ies of ~h~ transdermal patch, ~:~
eoP~rdising th~ adhesion of the ma~rix ~o the skin and the relia~le drug absorption. `~
The matrix of "monoli~hic" transdermal patches must ~herefore comply with severa~ prere~uisites. In f~ct the active ingredien~
must be provided by a notable thermodynamic poten~ial and nevertheless it must be stable in tim~. Sinc~ the matrix contains also the pressure sensitive adhesives which stick the patch ~o the skin, it mus~ have good "tack" pr~per~i~s..
SUBSTITUT~ Slt~ IET
WO93/1077~' 212 ~ ~ O PCT~EP92/0271~-1 Neverthaless the patch mu~t be easi ly removabl~ from the skin after use, and during this procedure ~he matrix must remain attached to the ou~er coveri ng and not to ~he ski n . The adhe~ives must not "creep", because in ~his c~se the patch would s~;ick to ~he container. As al ready pointed out, the matrix should nc~ con~ain ab~orption enhanç~rs, in or~er ~o prevent ~kin irrita~ion or sensi~isation. In addition, obviously, all the componenks of the ma~rix must b~3 wel 1 tolerated by the skin, even after repeated and prol onged appl i cati ons of th~ patches .
De~crlptis:~n of ~he pr~sent invention S~veral formulations were inves~igat~d in ord~r to optimize the matrix of the QTP described in this invention. Mos~ formulations were bas~d on acryl ic opolymers, to which differ~nt subs~ances were add~d in order ~o improv~ the adhesive qual ity of ~he matrix, for exarnple hydroabiethylalcohc)l, glycerylester of hydrat d col lophonium, pen~aester of hydrated col lc>phonium, methylester of partial~y hydrated collophonium, or ~-methylstyrol/s~yrol copolyrners. Al l these formul~tions had to be discarded because of crystallisation of ~he a ~ive ingredi~nt or impai rment of i~s release rate ~ -~ ~.Bas~d on this experience a monol ithic ma~rix was developed which represen~s a de~inite improvement over ~he present state of art, since it el iminates or reduces to a minimum ~h~ main di sadvantage~3 of the transdermal patches known up to now and . ., previously described. In ~act ~he nèw invention provides a system f~r the ~ransdermal administra~ion of estradiol which is well tolera~ed, is st ble, is effeçtiv~9 preven~s the crystallisation of the active ~ngredient ln the matrix, ensures adequate and extended levels of the active in~redien~ in blood, and has very good tack and adhesiYe properties.
SI~STITIJTE SH~T
WO~3/1077' ~ PCr/EP9~/02 A~cording to the invention the above mentioned features were provided by a transdermal patch for the ex~en~ed release of 17~-estradiol onto the ~;kin consisting of:
a) an outer covering (backing foil );
b) pressure-sensitive adh~sive copoiymers c~ns~it-ting ~he ma~rix in which the active ingredient is dissolved or dispersed ( drug reservoi r );
c) a protective liner which is removed at the time of use;
The i nven~i on descri bes a new transdermal patch for ~;he extended re~ase of es~radiol to the ~kin, in wt-ich the active ingredien~
s dissolved or dispers~d in a 5u-~able pressure-sensitiv~
adhesive copolymeric ma~rix, and which surpri~in~ly avoids the need of substances to improve the absorption of ~h~ drug through the skin (enhancers), or of supersaturated solutions o~ the active ingredient, thus preventing problems of skin comp~ti bi l i ty and of stabi l i ty of ~he who~ e sys~em.
A specific embodim~nt concerns a ~ransderrnal rnedic~t~d patch which is charact2rised in that the components of ~he adhesive copolymers are obtained by radical po~ymeri~ation of 2-ethylhexyl acrYlate, methyl acrylate, ac:rylic acid, vinyl acetatet hydro>~ethyl acrylate or mixture thereof, possibly with ~uantities o~ less than 0.5% (w/w) of other ad~itives in the adh~sive copolymers.
A specific embodiment of the invention conc~rns a transdermal medica~ed pa~ch in which the adhesive copolymers o~ ~he matrix ar~ obtained by radical polymerization of (w/w of the matrix) about 50% to 70% ~preferably 55% to 65% and especially 61g6 to 64%) 2-ethylhexyl acrylate, about 2096 to 40% (preferably 24% to 32% and ~special ly 25% t~ 28%) methyl acryla~e, about 2% ~o 8%
(preferab~y 3% to 5% a- especially 4% to ~g6) acrylic acid, abou~ 2% to ~ 0% ( preferabl y 3% tc> 796 and especi al 1 y 4X ~o 5% ) ~Jinyl acetate, and a~o~t 0.~% to 3% (preferably 0.7% to t~5% and especially abol-t 1%) hydroxyethyl acrylate.
SU~TlTlJT~ S~ T
WO 93/1077~ PCI /EP92/027~
?12'120~
Smal 1 quanti ti es of 1 ess than O . 5% of o~her subs~ances may al sc:
be uS~d to i mprove ~h adhesi ve prvperti es and the strength of the mat r i x .
~, According to the invent~on no cross-l inker is used in the adhesive copolyrrer9 such as titanium ac~3ty~as::etonate, as it is slJggested by the prior art3 in order to avoid creeping of khe adhesives onto the removable protective l iner and therefvre stic:king of the patch to its container. The pr~blem of creeping i s surpri si ngl y avoi ded i n the i nventi on by usi ng the desori bed copolymers obtained by radical polymerization.
The OTP according to the invention is characterized by a content.
o~ 17~-estradiol from lX to ~%, pref~rably 2.0% to 2.5%, (wJw3 o~ the weight o~ the adhesive copolymers.
., .
A speci~ic embodiment of the inventiQn concerns a transdermal patch which contains about 4 rmg 17i3-estradiol per 18 to 2Q cm2 of patch area.
A sp~cific embodi-ment of th~ invention of the trancdermal patch comprises an outer covering of suita~le proteetive mat rials, which forms the ext~rnal backing foi l o~ th~ patch and i~
constituted by a foi l of thin, ~lexible and water-impermeable material, preferably selected ~rom th group of polyest r~
polyure~hane, polyethylene andJor polyvinyl chloride.
Final ly, the transdermal pa~ch according to the inventien comprises a removable protec~ive liner, preferably consti~uted by a foil of paper or polyester which is preferably silicon~-coated on one or both sijdes and that is easily removed a~ the time of use without lmp~iring the ~ransdermal patch.
Accvrdiny to the additional emb~diment of the invention, a process is described for the production of a transdermal patch for the extended release of 17~ estradiol to the skin, which is characterized in that pressure-sensitive adhesive copolymers con~aining 1713-estradiot as active ingredient are spread on~Q a SUB~ 5T~
WO ~3/107, ' P(~/EP92/0271~
~12~U9 - 8-removable protective liner and then covt~red by ans:th~r . l.~ner which becomes the outer covering.
A~ternatively the pressure-sensitive adhesive sopolymers containin~ 17~-~s~radiol are spread on a water-impermeable ft~i l which be~om~s ..he outer covering7 and are then cover~d by the protec~ive l iner.
Sti l l alternativ~ly the pr~ssure sensitive adhesive copolymers containin~ t713-~stradiol are spread ~n an in~ermediate liner ~ usual l y a si 1 i coni zed paper sheet ) and ~hen covere~ by the foi l of the outer covering ~o which the copolymers adhere firmly. In the final manufa~turing process the intermediate liner is removed and subs~i~uted by ~he protective liner.
A~cording to a pref~rred embodimen~ of the claimed proces~ the ~ransdermal patch can be produced as fol7~ws: ;
- the pressure-sensitive adhesiYe copolymers ar~ dissolved in an :~
or~nic solvent ~adh~sive mixkure~
17~-estradiol 9 dissolv~d or dispersed in an organic sol~ent or in a mixture of solvents, is dissolved or dispersed in the adhesive mixture by stirring, at a concentration ~rom lX to ~%
(w/w) of ~he dry weight of the pressure-sensitiv~ adhesive copolymers;
- the ob~ained mixture is concen~rated by ~vaporation of some of the s~vents and then spread onto ~he removable pro~ective liner, preferably constituted by a foil of p~per or polyester which isi silicone-coa~id on ~ne or on both sides;
alternatively the mixture is spread on~o the foil of th~ outer covering, constituted by water-im~ermeable materials preferably selected from thei group of po ester, polyurethane7 polyethylene and/or polyvinyl chloride; still al~ernative~y the mixture is spread on an intermediate liner, preferably constitu~ed by a sheet of paper, prefeirably siliconized on one or on both sides;
~r~ 3~
WO93/1077' 21 2 ~1~; 9 PCT/EP92/027~
_ 9 _ - ~he solven~ is evaporated a~ a-~emperature frvm 30' ~o ~O'C
with or without applying a vacuum;
- a ~o11 o~ thin, flexible and wa~er-impermeable material constituting the outer covering is applied, or, alternatively the final proteetive lin~r is appii~d or alternatively the intermediate liner is removed and replaced by the final protectiv~ liner, according one of the three procedures outlined above as examples, - the produced composite medica~ed foi 1 is cu~ into portions of appropriate shape and surface, such ~hat they contain the requirsd ~uantity of the active ingredient suitable for the therapeutic use, and in ~his way th~ final transdermal pa~ch~s are obtai ned .
The appropriate qual i~ative-qua7~itatiYe selection of th~
acryl ic component of the ~inal c opolymer sbtained by radical polym~rization, i.e. 2-e~;hylhexyl acrylate, acrylic acid and hydroxyethyl acrylate, and of vinyl acetate whiGh acts as solvent ~or the active ingredien~, is suitable for a transderm~
system for the extended release of es~radiol which is s~cable in tirne and eloes not give rise to crystal 1 isation of the active i ng red i ent i n the mat r i x .
Moreover, as will be described below, the serum levels of estradi~l in menopausal pa~ients obtained after having applied ~he ~ransdermal patch to their skin7 are more constan~ during ~he application time than during the applicatt~n of a patch proYided wi~h a diffusion-rate limiting membrane and ethanol as enhancer. Surprisin~ly the extent of absorption ~fter the applicatlon of the invented OTP was similar to that of the enhanced system.
Sl~.~BSTlT~JTE~ SHEET
WO93/1077' PCT/EP92~027fl~
~ t~i 9 -- ~o Example 1 (Production of a ~ransd~rmal pa~ch con~aining ~ ~9 of estradi~
The production process of the transdermal patch according to the present invention, con~aining 4 mg o~ 17~e ~radiol a~ the active tngredient per t8 cm2 of pa~ch area (hereinafter referr~d to as "DERMESTRIL"), is illustrated further by the ~ollowing9 non-limiting example.
An adhesive mixture was prepared diss~lvtng in 3 ~itres of ethylacetate a mixture of copolymers obt~ined by radical polymeri~ation of 1038 9 2-ethylhexyl acrylate, ~20 9 methyl acrylate, 6~ 9 acrylic acid, 87 9 vinyl ac~ta~, and 17 9 hydroxyethyl acrylate.
A quantity of 40 9 of 17~ estradiol was dissolved or finely suspended in a mix~ure of solven~s cons~i~uted by 1 litr~ of propan-2-ol and 1.5 litr~s of ethyl a~etate~ This solution was added~ under stirring, to ~he mix~ure of copolymers, prepared as described above.
The mixture was sti rred until a homogeneous mass was obtained and this was euaporated to produce a mixture with a conslst~ncy appropriate for spreading on the appropriate liners. Th~n the adhesive mixture cont~ining the active ingredien~ was spread onto a foil of silicone-coa~ed paper or polyester and dried at a temperature b@kween 30 and 80'C ~o produce a fi~m of matrix wei ghing about 98 g/m2 ~ 5X) as the dry weight, corresp~nding to about 2.2 g of 17~-es~radiol p~r m2 of the dry matrix.
Finally, a polyester foil, about 15 ~m thick, was stuck on the matrix to form the outer covering of the patch.
Individual circular patches having areas of ~8 cm2, each c~n~ining about 4 mg of ~he ac~ive ingredient were cut from the comp~site mediçated foil to form ~he final transdermal patch.
Sl)BSTITlJTE SHEET
WO 93/1077' PCT~EP92/0~7l~
? ~ 2 ~ ~
In ~ummary, the step~ for preparing the estradiol transdermal patch (OTP) as~cording ~o ~he present invention consist substanti al i y of ~
- adding a solution or a fine susp~nsion of estradiol to a suitable mixture o~ copolyrn~3rs of acrylates and vinyl acetate;
- spreading a thin layer of the mixture formed by the dispersion of the active ingredient in the acrylic copolymers on a protec~ive 1iner of silicone-cc~ated paper or polyester to be removed at the ti me of use;
- drying the liquid adhesive film formed by the acrylic copolymers and containin~ estradiol, at a temperature between 3{~ and 80'C in order to ~vapora~e thf~ solvent~ wi~h or without applying vacuum;
- applying a foil of thin, flexible, water imperme~ble material which constitutes the outer coverins of the pa~ch;
- cutting the composite m~dicated foi 1 prod~ced as above described into portions having ~he desired shape and surface, tor .oxample 18 cm2 for patchesl containin~ 4 mg est;radiol;
- alternativ~ procedures are also possible, such ~s spreading the adh~siYe mtx~ure onto the ou~r covering or onto an intermediate liner. The ~ollowing manufaeturing steps are ~hen made in order to produce the appropriate final composite med i cated f o i 1 .
Release of es~radiol in vitrc .
The release of estr~diol from the OTP produced according to the invention ( "DEP~MESTRIL" ) was tested in vitro wi~h the fol lowin~
p rocedu re .
SUB~ UT~ SHE~
, . .. .. .... ,, .. .. , ... . " , , WO 93/11~77' PCT~EP92/0271~
4~
Discs cut from l)ERMESTR~L OTP, with surfaçe ar~as of 6 cm2 and containing about 1.33 mg of estradiol, were applied to a support deposited on the base of the dissolu~lon test apparatus according to USP XXII, consisting of a 1 litre g1ass vessel and ~-;
a rotati ng bl ade .
The di stance between the supps: r~ and ~he bl ade, whi ch rotated at a speed of 50 revol Utl ons per mi nute ~ was 2 . 5 cm and the dissolution l iquid was constituted by ~00 ml of water at 32C.
Portions of 1 ml of the solution were withdrawn at ~!7 4, 6, 8, 12, 24 and 36 ho~rs after the start of the ~xperiment, and the estradiol cc:ntent was determined by HPLC. The test was r~3peated ~;
6 times. `
The quantities of released estradiol, expressed as mi l l i~rams ::
and as percent of the nominal ~ontent of estradiol in DERMESTRIL
at the various times, are given in tabl~
Tabl e Mi l l igrams and percen~ v~ es~radiol released in the in vitro test :
T i me ( h ) mg X of nomi na 7 2 0.6~ 16.5 4 o.95 ~3.
6 1.25 31.2 12 1.70 42.5 . ;~
~4 ~ . 48 6~ . 9 36 3.20 80.
Table 1 ~hows thak frs:)m 6 to 36 hours, the release kinetics is l i near and can be expressed by the equati on R = O . 8966 + O . 0646 x h -~
where ~ _ mg of estradiol released and h - ttme in hours.
SL~ r,~ Z " ~
W093/1077' PCT/EP92/027W
- 13 ~ ~ 2 ~ ~ ~ 9 Table 1 shows also tha~ abowt 30x of the estradiol contained in ~-.
the patch had been released after 6 hours, abou~ 60% aft~r 24 :-hours and about 80% after 36 hours.
Bioavailability of estradiol from DERMESTRIL
The bioavailability s~udy was carried out in postmen~pausal women. DERMESTR~L was compared with an OTP commercially available and characterized by a diffusion rate limi~ing membranP and containing e~hanol as solvent and absorption enhancer (hereinafter called "Reference OTP"). ~-~
., .~ ., Two DERMES~RIL patches prep~red according to the invention, and containing each 4 mg of estradiol per 18 ~-m2 or tWQ Ref~rence OTPs, also containing 4 m~ of estradi~l, were applied on ~h~ :
skin of the s~bject for a ingle application of 96 hours. i:
Studied were 20 subjects and ~he patches were applied according ::
to a cross over design, with a suitable wash-ou~ period be~ween the two treatments.
Estradi~l in blood serum was de~ermined~by a RIA method. The estradiol serum levels ~xpressed in pg/ml are given in figure l and in table 2. Tabl~ 2 gives ~lso the avera~es of the maxtmum . ~
: concentrations found ~C~.x), of the times to ~he pe~k (~x) and ~.
of the area under the c~ncentration/~ime curve: (AUC) in the period 0-96 hours after administra~ion.
":
Sl~E3S~lTUTE SHIEET
WO 93/1077' PCr/EP92/027~ t 3~ - 14 - ~ ~
Tabl e 2 :~
Estradiol levels in serum at various times ~fter the ap~lication of 2 OTPs a~cording to the invention (DFRMESTRIL) or of 2 commercial OTPs (R ference OTP~, Both, D~RMESTRIL and khe :
Reference OTP contain each 4 m~ estradiol. Avera~es and SD of 20 subjects, Estradi ol pp/ml + S~
Hours DERMESTRIL Re~erenGe OTP
O t.96 + 3.94 2.06 ~ 3.81 2 5.34 + 7.B7 31.13 ~ 29.45 ~:
2~.27 + 34.~4 67.65 ~ 4~.~7 8 42.46 ~ 31.~2 6~.91 ~ 2~.86 12 ~5.07 + 46.51 61.35 + 21.26 24 ~1.8~ + 28.63 5~.35 ~ 16.76 36 56.28 ~ 32.87 61.37 + 23.31 48 44.43 ~ 24.13 49.34 + 1~.37 47.74 ~ 39.17 42.78 + 21.19 72 41.02 ~ 22.29 30.48 ~ 15.34 84 4Q.03 + 19.87 22.33 ~ 12.87 :~
96 3~.18 + 19.73 19.85 ~ 9.16 ~`
~08 8.80 ~ 6.51 7.49 + ~.39 120 7.01 ~ 5.91 5.76 + 4.89 ~:
C~x 66.1B + 4~.0 87.35 + 29.87 t~x 35.00 + 19.8 1~.80 + 18.99 ~
AUC ~O-g6 h) 4286 ~ 2409 4268 + 1226 ~-From the results given in table 2 it can be ~.~ncluded that th~
areas under the concentration/time curves (AUC) do not differ significantly aft~r the two ~reatmen~s. In fact the A~C10-96 after DERM~STRIL was 4286 ' ~409 (SD;, and after the Reference OTP was 4268 ~ 1226 (SD).
.~II~ ~TI~II~ ~ ~T `:
WO 93/l077~ PCI /EP92/02711 1 5 - ~ " 3 This ~emonstrates that th~ bioavai labi l ity of estr~diol ~rom ::
DERME~TRXL is the same as that ~rom Reference OTP, and this is a surprisin~ result because DERMESTRIL does not contain absorption enhancers . : ~
Tolerabi l ity by the skin ~-:
The skin tolerability to th~3 C)TP prepared according to the inven~ion was evalua~ed on 10 ~emale guinea pigs weighing between 300 and 400 9. ~-~
The patches were applied to the previously shaved l@f~ scapular region of the animals. An area of patch o~ 2 x 2 cm cut from DERMESTRIL and ~hus containing about 0.~9 mg ~stradiol, was --~
stuck on the shaved skin and l~fl; there fGr about 6 hours. The :
tolera~ility o~ the patch was eva~ua~ed by the appearance of erythema or oedsma after 24 hours of appl ica~ion, according to the fol lowing s~ore~.
Score ERYTHEMA OEDEMA
0 No ef f ect NQ ef f ect Sl i 9ht Sl i ght oedema ~- .
Moderate Modera~e o~dema ~;
3 Intense Severe oedema The test was repea~ed usi ng the same ~;cores after 7 days, i n -~
order ~o re~:ord a possible sensitization induced by the pat~h" ~
-'-"~, The overal 1 swm o~ the scores relating to erythema for the 10 animals was 1 o~ 30, because only 1 animal out of 10 showed a sl ight erythema (30 is the maximum score obtainable) .
No ~nimal presented oedema. ~;
. . .':
SUB~;TITIJTF SH~-~T ~
WO 93~'1077' PCI /EP92~0271i~1 ., In the sensi~isa~ion challenge carried out a~ter 7 days, no an1mal had eryth~ma or oedf~ma, demonstra~in~3 ~hat the patches were wel 1 tolerated and did not induc~ sensi~i~ation under the ex pe r i me nta l cQnd i t i ons .
,.
Examples 2 t~ 4 and Comparative Examples 1 to 7 Table 3 summarizes th~ composi~ion of the matrix of Exa~mples 1 ~o 4 and o~ the C:omparative Examples 1 to 7. The correspondin~
formulations of the matrix containing the cop:>lymers obtained by radical p~lym~rization of the acryl ic compounds are :
quantitatively listed in table 3. Th@ resull;ing OTP~ were tested ;~
for stabi 1 ity and also~ in six human subjects, for adh~sion and -:
skin compatibil~y. The resul~s obtatned with ~he ~leven formulations 3re also reported in ta~le 3.
The resullts clearly show that ~ ormulations No~ 1 ~o 4 and ~:
partiGularly No. 1 exhibit the propert1es require~ for the ~-matrix o~ a "monol ithic" ~ransdermal patch. Conv~rsely oth~r formulations, wh:ich are here l is~ed as Comparative Examples 1 ~o 7, had disadvantage~, for instance discolouration (fort...Jlations No. 6 ~o ~0), unacceptahls skin compatibility (formulation No. ;:
5), ~r una~ceptable tack properties tformulations No. 6, 7, 9 ~-~
and 11 ).
S~ T~3TE ~
W0~3/1077 PCT/EP92/0271~
. ' ` ' ;.;.~. ~J ' - 1 7 ~
Table 3 -~.~
Percentage of monomers in~t~ acrylic copolymers and other substanc~s in differen~ f~rmulations. Properties of the matrix obtained wi~h these copolymers.
Examples Comparative Examples 1 2 3 4 ~ 2 3 4 5 6 7 F~rmulation N~. 1 2 3 4 5 6 7 R 9 10 1 Substances 2-EHA 62.6 6~.5 63.4 57.6 66.9 62.2 63.1 64.0 59.2 56.6 64.2 MA 26.4 33.0 ~05 19.5 0.0 26.4 21.5 16.5 25.1 24.0 16.5 VA 5.6 0.0 9.~ 8.9 28.0 5.6 9.8 1~.0 5.3 5.1 14.0 :~
AA 4.4 5.~ 3.6 3.3 0.0 4.3 3.~ 2.7 4.1 3.9 2.8 ~-GMA 0.0 0.0 0.1 0~1 0.2 0.1 0.1 0.1 0.~ 0.0 0.1 HEA 1.0 0.0 1.8 1.6 5.0 1.0 l.B 2.5 1.0 0.9 2.5 -~
TA 0.0 0.0 - 0-0 0.4 0-3 0.3 0.4 0-4 HR 0.0 0.0 0.0 9.1 0.0 O.o 0.0 0.0 4.8 9.1 0.0 ;;
Fea~ures Estrad. solub. ~ G G G G G G ~ G G G
Discolora~ion ~ + ~ + +
Tack on skin G G M G G B B G B G
Ski n ~ompat . G M M M B G G M G M G .-Legenda: B = Bad; M = Medium; ~ = Good; S = Too strong;
= Presen~; - = Absen~ -Su~stances~
2-E~A = 2-Ethylhexylacrylate MA = Methylacrylate YA - Vi~yl acetate AA = Acrylic acid ~ .
GMA = Glycidylmethacryla~e :
HEA = Hydroxye~hylacry la~e TA = T i tan i um acety 1 acetonate :~
HR = Hydrocarbon resin ,.
.. , . :~.
. ., SL113STITUTE S~IEET -
Claims (9)
1, A transdermal medicated patch for the extended release of 170- estradiol to the skin, consisting of pressure-sensitive adhesive copolymers in which the active ingredient is dissolved or dispersed (matrix), supported by a water-impermeable foil (outer covering) and covered by a protective liner that is removed at the time of use, characterized in that the pressure-sensitive adhesive copolymers are obtained by radical copolymerization of (w/w of the matrix) - about 50 to 70 % 2-ethylhexyl acrylate, - about 20 to 40 % methyl acrylate, - about 2 to 8 % acrylic acid, - about 2 to 10 % vinyl acetate and - about 0.5 to 3 % hydroxyethyl acrylate.
2. A transdermal medicated patch according to claim 1, characterized in that the pressure-sensitive adhesive copolymers are obtained by radical copolymerization of (w/w of the matrix) - 55 to 65 % and especially 61 to 64 % 2-ethylhexyl acrylate, - 24 to 32 % and especially 25 to 28 % methyl acrylate, - 3 to 5 % and especially 4 to 5 % acrylic acid, - 3 to 7 % and especially 4 to 5 % vinyl acetate and - 0.7 to 1.5 % and especially about 1 % hydroxyethyl acrylate.
3. A transdermal medicated patch according to claim 1 or 2, characterized in that other substances are added to the adhesive copolymers in quantities less than 0.5 % (w/w) of the matrix.
The original claims 4 to 9 follow.
The original claims 4 to 9 follow.
4. A transdermal medicated patch according to any of claims l to 3, characterized by a content of 17.beta.-estradiol from 1% to 5%
and preferably 2.0% to 2.5% by weight of the adhesive copolymers.
and preferably 2.0% to 2.5% by weight of the adhesive copolymers.
5. A transdermal medicated patch according to any of claims 1 to 4, characterized by a content of about 4 mg 17.beta.-estradiol per 18 to 20 cm2 of patch area.
6. A transdermal medicated patch according to any of claims 1 to 5, characterized in that the patch comprises a removable protective liner, preferably constituted by a sheet of paper which is preferably silicone-coated on one or both sides.
7. A transdermal patch according to any of claims 1 to 6, characterized by an outer covering constituted by a foil of a water-impermeable material, preferably selected from the group of polyester, polyurethane, polyethylene and/or polyvinyl chloride materials.
8. A process for the production of a transdermal medicated patch according to any of claims 1 to 7, characterized in that pressure-sensitive adhesive copolymers containing 17.beta.-estradiol as active ingredient are spread onto a removable protective liner and then covered by an outer covering.
Alternatively the pressure-sensitive adhesive copolymers containing 17.beta.-estradiol are spread in the foil of outer covering and eventually covered by the protective liner in the final steps of production, Alternatively, the pressure-sensitive adhesive copolymers containing 17.beta.-estradiol are spread onto an intermediate liner and then covered by the foil of the outer covering to which the copolymers adhere firmly.
According to this procedure in the final step the intermediate liner is removed and replaced by the protective liner.
Alternatively the pressure-sensitive adhesive copolymers containing 17.beta.-estradiol are spread in the foil of outer covering and eventually covered by the protective liner in the final steps of production, Alternatively, the pressure-sensitive adhesive copolymers containing 17.beta.-estradiol are spread onto an intermediate liner and then covered by the foil of the outer covering to which the copolymers adhere firmly.
According to this procedure in the final step the intermediate liner is removed and replaced by the protective liner.
9. A process for the production of a transdermal medicated patch according to claim 8, characterized by the following procedure:
- the pressure-sensitive adhesive copolymers are dissolved in an organic solvent to form an adhesive mixture;
17.beta.-estradiol, dissolved or finely suspended in an organic solvent or in a mixture of solvents, is dissolved or dispersed in the adhesive mixture by stirring at a concentration from 1% to 5% (w/w) of the dry weight of the pressure-sensitive adhesive copolymers;
- the mixture obtained is optionally concentrated by evaporation of some of the solvent and is then spread onto a removable protective liner, preferably constituted by a sheet of paper, preferably silicone-coated on one or both sides, - alternatively the adhesive mixture is spread on the foil of the outer covering and eventual covered by the protective liner in the final steps of production, or alternatively the adhesive mixture is spread on an intermediate liner which is then covered by the foil of the outer covering to which the copolymers adhere firmly.
According to this procedure in the final step the intermediate liner is removed and replaced by the protective liner;
- the residual solvent is dried at a temperature from 30 to 80°C, with or without applying a vacuum;
- a foil of thin flexible and water-impermeable material constituting the outer covering of the patch is applied on the layer of adhesive matrix, or, alternatively, the foil of the protective liner is stuck on the adhesive matrix spread on the outer covering, according to the first steps of the production process above described, and - the composite medicated foil produced as above described is cut into portions of appropriate shape and dimensions such that they contain the quantity of the active ingredient required for the therapeutic use.
- the pressure-sensitive adhesive copolymers are dissolved in an organic solvent to form an adhesive mixture;
17.beta.-estradiol, dissolved or finely suspended in an organic solvent or in a mixture of solvents, is dissolved or dispersed in the adhesive mixture by stirring at a concentration from 1% to 5% (w/w) of the dry weight of the pressure-sensitive adhesive copolymers;
- the mixture obtained is optionally concentrated by evaporation of some of the solvent and is then spread onto a removable protective liner, preferably constituted by a sheet of paper, preferably silicone-coated on one or both sides, - alternatively the adhesive mixture is spread on the foil of the outer covering and eventual covered by the protective liner in the final steps of production, or alternatively the adhesive mixture is spread on an intermediate liner which is then covered by the foil of the outer covering to which the copolymers adhere firmly.
According to this procedure in the final step the intermediate liner is removed and replaced by the protective liner;
- the residual solvent is dried at a temperature from 30 to 80°C, with or without applying a vacuum;
- a foil of thin flexible and water-impermeable material constituting the outer covering of the patch is applied on the layer of adhesive matrix, or, alternatively, the foil of the protective liner is stuck on the adhesive matrix spread on the outer covering, according to the first steps of the production process above described, and - the composite medicated foil produced as above described is cut into portions of appropriate shape and dimensions such that they contain the quantity of the active ingredient required for the therapeutic use.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITTO91A000907 | 1991-11-25 | ||
| ITTO910907A IT1253265B (en) | 1991-11-25 | 1991-11-25 | ACRYLIC-BASED ADHESIVE COPOLYMER MATRIX PREPARATION FOR THE TRANSDERMAL EXTRADIOL RELEASE. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2124209A1 true CA2124209A1 (en) | 1993-06-10 |
Family
ID=11409742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002124209A Abandoned CA2124209A1 (en) | 1991-11-25 | 1992-11-24 | A new preparation with an acrylic-based adhesive copolymeric matrix for the transdermal delivery of estradiol |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US6156335A (en) |
| EP (1) | EP0614356B1 (en) |
| JP (1) | JPH07501335A (en) |
| AT (1) | ATE128029T1 (en) |
| AU (1) | AU666151B2 (en) |
| CA (1) | CA2124209A1 (en) |
| DE (1) | DE69205010T2 (en) |
| DK (1) | DK0614356T3 (en) |
| ES (1) | ES2078066T3 (en) |
| GR (1) | GR3018303T3 (en) |
| IT (1) | IT1253265B (en) |
| WO (1) | WO1993010772A1 (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5554381A (en) * | 1993-08-09 | 1996-09-10 | Cygnus, Inc. | Low flux matrix system for delivering potent drugs transdermally |
| DE4333595A1 (en) * | 1993-10-01 | 1995-04-06 | Labtec Gmbh | Transdermal therapeutic system for applying drugs to the skin |
| GR1002079B (en) * | 1994-07-26 | 1995-12-05 | Lavipharm A E | System of a special structure and composition for the rapid transdermal administration of oestrogens. |
| DE19526864A1 (en) * | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
| DE19600347A1 (en) * | 1996-01-08 | 1997-07-10 | Lohmann Therapie Syst Lts | Skin-adhering pharmaceutical preparation, in particular TTS for the delivery of 17-beta-estradiol to the human organism |
| US6623763B2 (en) | 1996-01-08 | 2003-09-23 | Lts Lohmann Therape-System Ag | Pharmaceutical preparation adhering to the skin, in particular a transdermal therapeutic system for the release of 17-β-estradiol to the human organism |
| DE19830649C2 (en) * | 1998-07-09 | 2003-04-10 | Lohmann Therapie Syst Lts | Topical patch with nonsteroidal anti-inflammatory drugs with acid group |
| GB0019745D0 (en) * | 2000-08-10 | 2000-09-27 | Univ Surrey | Gene expression element |
| WO2002045701A2 (en) * | 2000-12-05 | 2002-06-13 | Noven Pharmaceuticals, Inc. | Crystallization inhibition of drugs in transdermal drug delivery systems |
| DE10141652B4 (en) | 2001-08-24 | 2011-04-07 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system based on polyacrylate pressure-sensitive adhesives without functional groups and its use |
| US6927267B1 (en) | 2002-03-07 | 2005-08-09 | Basf Ag | High solids dispersion for wide temperature, pressure sensitive adhesive applications |
| DE10229733A1 (en) * | 2002-07-02 | 2004-01-22 | Basf Ag | Pressure sensitive adhesives for carriers made of soft PVC |
| AU2003254834B2 (en) | 2002-08-09 | 2009-02-19 | Fuso Pharmaceutical Industries, Ltd. | Female hormone-containing patch |
| AU2005291098B2 (en) * | 2004-10-04 | 2011-11-24 | L'oreal | Cosmetic and/or dermatological composition for sensitive skins |
| FR2889057B1 (en) * | 2005-08-01 | 2008-07-18 | Oreal | COSMETIC AND / OR DERMATOLOGICAL COMPOSITION FOR THE PREVENTION AND / OR TREATMENT OF SENSITIVE OR DRY SKINS |
| US7754256B2 (en) * | 2007-03-07 | 2010-07-13 | Stan Dennison | Nutritional composition |
| US20080226698A1 (en) * | 2007-03-16 | 2008-09-18 | Mylan Technologies, Inc. | Amorphous drug transdermal systems, manufacturing methods, and stabilization |
| FR2919501B1 (en) * | 2007-08-02 | 2010-12-31 | Oreal | USE OF HESPERIDINE OR ONE OF ITS DERIVATIVES FOR THE PREVENTION AND / OR TREATMENT OF RELEASED SKINS |
| FR2920304B1 (en) * | 2007-09-04 | 2010-06-25 | Oreal | COSMETIC USE OF LYSAT BIFIDOBACTERIUM SPECIES FOR THE TREATMENT OF DROUGHT. |
| BRPI0816214B8 (en) * | 2007-09-04 | 2017-12-26 | Oreal | cosmetic use, cosmetic and / or dermatological composition, and methods for the cosmetic treatment of the skin, for the cosmetic treatment of skin signs of aging and / or photoaging, and for the cosmetic treatment to prevent and / or treat dry keratinous substances. |
| DE102008013701A1 (en) | 2008-03-11 | 2009-09-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with stabilized membrane |
| NZ589542A (en) * | 2008-05-30 | 2012-10-26 | Mylan Inc | Transdermal drug delivery system comprising an active agent in amorphous form and polyvinylpyrrolidone |
| US8231906B2 (en) | 2008-07-10 | 2012-07-31 | Noven Pharmaceuticals, Inc. | Transdermal estrogen device and delivery |
| KR20110082142A (en) * | 2008-10-06 | 2011-07-18 | 밀란 테크놀로지즈 인코포레이티드 | Amorphous rotigotine transdermal system |
| DE102008059054A1 (en) | 2008-11-26 | 2010-05-27 | Otto Bock Pur Life Science Gmbh | Polyurethane patch for the transdermal application of active substances and process for its preparation |
| WO2011009800A1 (en) * | 2009-07-21 | 2011-01-27 | Basf Se | Film-to-film laminate, made by using an aqueous polymer dispersion as adhesive agent |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4906475A (en) * | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
| DE68917292T2 (en) * | 1988-02-26 | 1995-02-02 | Riker Laboratories Inc | TRANSDERMAL ESTRADIOL AS A THERAPEUTIC SYSTEM. |
| US4994267A (en) * | 1988-03-04 | 1991-02-19 | Noven Pharmaceuticals, Inc. | Transdermal acrylic multipolymer drug delivery system |
| EP0484543B1 (en) * | 1990-04-24 | 1995-12-13 | Teijin Limited | Plaster |
-
1991
- 1991-11-25 IT ITTO910907A patent/IT1253265B/en active IP Right Grant
-
1992
- 1992-11-24 JP JP5509788A patent/JPH07501335A/en active Pending
- 1992-11-24 AU AU29451/92A patent/AU666151B2/en not_active Ceased
- 1992-11-24 AT AT92923782T patent/ATE128029T1/en not_active IP Right Cessation
- 1992-11-24 WO PCT/EP1992/002704 patent/WO1993010772A1/en active IP Right Grant
- 1992-11-24 DE DE69205010T patent/DE69205010T2/en not_active Expired - Lifetime
- 1992-11-24 US US08/244,132 patent/US6156335A/en not_active Expired - Fee Related
- 1992-11-24 ES ES92923782T patent/ES2078066T3/en not_active Expired - Lifetime
- 1992-11-24 DK DK92923782.4T patent/DK0614356T3/en active
- 1992-11-24 CA CA002124209A patent/CA2124209A1/en not_active Abandoned
- 1992-11-24 EP EP92923782A patent/EP0614356B1/en not_active Expired - Lifetime
-
1995
- 1995-12-05 GR GR950403422T patent/GR3018303T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0614356B1 (en) | 1995-09-20 |
| GR3018303T3 (en) | 1996-03-31 |
| DE69205010T2 (en) | 1996-02-22 |
| US6156335A (en) | 2000-12-05 |
| AU2945192A (en) | 1993-06-28 |
| WO1993010772A1 (en) | 1993-06-10 |
| DE69205010D1 (en) | 1995-10-26 |
| ES2078066T3 (en) | 1995-12-01 |
| ITTO910907A0 (en) | 1991-11-25 |
| IT1253265B (en) | 1995-07-14 |
| DK0614356T3 (en) | 1995-11-13 |
| ATE128029T1 (en) | 1995-10-15 |
| JPH07501335A (en) | 1995-02-09 |
| AU666151B2 (en) | 1996-02-01 |
| ITTO910907A1 (en) | 1993-05-25 |
| EP0614356A1 (en) | 1994-09-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2124209A1 (en) | A new preparation with an acrylic-based adhesive copolymeric matrix for the transdermal delivery of estradiol | |
| US10709669B2 (en) | Microreservoir system based on polysiloxanes and ambiphilic solvents | |
| US8821920B2 (en) | Therapeutic patch for transdermal delivery of capsaicin | |
| JP2550441B2 (en) | Skin permeability promoting composition | |
| DK175328B1 (en) | Process for Preparing a Transdermal Nicotine Patch and a Transdermal Nicotine Patch | |
| US5364628A (en) | Pharmaceutical compositions | |
| EP0272987B1 (en) | Resilient transdermal drug-delivery device and compositions and devices employing fatty acid esters/ethers or alkanediols as percutaneous absorption enhancers | |
| EP0871420B1 (en) | Triacetin as a transdermal penetration enhancer | |
| US6162456A (en) | Adhesive transdermal drug delivery matrix of a physical blend of hydrophilic and hydrophobic polymers | |
| US20020012695A1 (en) | Transdermal preparation containing hydrophilic or salt-form drug | |
| FR2717689A1 (en) | Transdermal matrix system for administering an estrogen and / or progestin based on styrene-isoprene-styrene copolymer. | |
| JPH09501398A (en) | Active ingredient patch | |
| US20010009673A1 (en) | Transdermal therapeutic systems | |
| JPH07506562A (en) | Vegetable oil-based skin permeation enhancer compositions and related methods and systems | |
| CA1257837A (en) | Topical pharmaceutical compositions | |
| ES2504065T3 (en) | Stable Rasagiline Composition | |
| JPH02233621A (en) | Percutaneous absorbefacient and medicinal pharmaceutical containing the same for external use | |
| EP0315217B1 (en) | Pharmaceutical compositions | |
| IE69475B1 (en) | Pharmaceutical compositions | |
| JPH05286851A (en) | Application agent for treating disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |